HD Lighthouse Contributing Editor's Comment: The Lighthouse has been following research with creatine for some years now. It's encouraging to learn that leading researchers feel that it may become the cornerstone in an HD cocktail.

The authors review the reasons why creatine is so promising, including creatine's involvement in energy metabolism, impairment of which is almost certainly a key disease pathology, and the preclinical studies with mouse models that the Lighthouse has been reporting. Creatine has been shown to be safe and well tolerated in HD patients.

So why aren't there currently any Phase III clinical trials with creatine? The authors discuss the dosing issue. It may be that the doses tested so far with HD patients (5 g and 10 g) are too low. Ongoing studies are expected to clarify this soon.

Secondly, the authors are calling for preclinical studies of creatine in combination with other potential treatments. By reviewing the HD research projects funded by the National Institute of Neurological Disorders and Strokes, the Lighthouse has learned that Dr. Ferrante received funding for a stud expected to run from January 2004 through December 2008 to do combination trials with the R6/2 mice. He plans to start with creatine and CoQ10 and then begin adding other compounds, with cysteamine a high priority.

While combination trials with mice will undoubtedly give us some valuable information, it is the position of the Lighthouse's editorial staff that Phase III combination trials should start immediately with HD patients.
--Marsha L. Miller, Ph.D.
Posted to the HDL: 12 Aug 2005

The therapeutic role of creatine in Huntington's disease.

H. Ryu, HD Rosas, SM Hersch, and RJ Ferrante

Huntington's disease (HD) is an autosomal dominant and fatal neurological disorder characterized by a clinical triad of progressive choreiform movements, psychiatric symptoms, and cognitive decline. HD is caused by an expanded trinucleotide CAG repeat in the gene coding for the protein huntingtin. No proven treatment to prevent the onset or to delay the progression of HD currently exists. While a direct causative pathway from the gene mutation to the selective neostriatal neurodegeneration remains unclear, it has been hypothesized that interactions of the mutant huntingtin protein or its fragments may result in a number of interrelated pathogenic mechanisms triggering a cascade of molecular events that lead to the untimely neuronal death observed in HD. One putative pathological mechanism reported to play a prominent role in the pathogenesis of HD is mitochondrial dysfunction and the subsequent reduction of cellular energy. Indeed, if mitochondrial impairment and reduced energy stores play roles in the neuronal loss in HD, then a therapeutic strategy that buffers intracellular energy levels may ameliorate the neurodegenerative process. Sustained ATP levels may have both direct and indirect importance in ameliorating the severity of many of the pathogenic mechanisms associated with HD. Creatine, a guanidino compound produced endogenously and acquired exogenously through diet, is a critical component in maintaining much needed cellular energy. As such, creatine is one of a number of ergogens that may provide a relatively safe and immediately available therapeutic strategy to HD patients that may be the cornerstone of a combined treatment necessary to delay the relentless progression of HD.

Tracked on the Lighthouse:
creatine

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Source: Pharmacol Ther. 2005 Jul 28

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